The process of signal transduction across the lymphocyte plasma membrane is under investigation. Novel fluorescent probes of physiologic parameters such as membrane potential, intracellular free ionized calcium, and intracellular pH, in conjunction with the high sensitivity and single cell resolution of flow cytometry, are being utilized. These studies have revealed extensive !feed-forward and !feed-back regulatory relationships between ion channel opening, membrane potential, activity of the calcium pump, and rate of phosphatidyl inositol turnover. These mechanisms differ in the T, B and monocyte/granulocyte lineages. The process of signal transduction in thymocyte differentiation is being examined.